In the current funding period of our study entitled 'The Molecular Epidemiology of Ovarian Cancer' (RO1CA176016, PI: Dr. Schildkraut,), we have studied the relationship between candidate genes in the DNA damage and repair pathway and ovarian cancer risk using data from the North Carolina Ovarian Cancer Study (NCOCS). To date, we have examined the relationship between 53 genes and 652 SNPs in this pathway. The first phase of our study we have identified strong association between genes on the DNA repair pathway and ovarian cancer risk. In this competitive renewal we propose to expand the scope of our Phase 1 genotyping to further investigate genes the DNA repair and apopotosis pathways and to mount a second candidate gene association study. We hypothesize that a subset of the previouslyexamined SNPs in genes with known roles in DNA damage and repair will emerge as risk factors for ovarian cancer, and that newly-examined SNPs in genes within this and related pathways will be associated with risk of ovarian cancer. The proposed study will be designed to optimally accumulate evidence on candidates while simultaneously reducing the false positive rate among included SNPs and minimizing the rate of false negatives. Analyses will examine risk modification across subgroups defined by age, race, body mass index, oral contraceptive use, pregnancy history, histology and other exposures. The ultimate goal is to improve our ability to identify women at genetic risk of ovarian cancer and to design targeted intervention strategies to prevent this fatal disease. To this end, we propose to genotype in 2,075 invasive serous epithelial ovarian cancer cases and 2,075 age-matched controls of European descent to determine the relationship between genetic variants in DNA response and repair and related pathways. We will evaluate the association between over 2,000 SNPs with risk of ovarian cancer. We will access subjects from six independent case-control studies: North Carolina (Dr.Schildkraut), the Mayo Clinic (Dr. Goode), New England (Drs. Terry and Cramer), Pittsburgh (Dr. Ness), Los Angeles (Drs. Pearce and Wu) and Seattle (Dr. Rossing). Further confirmation will be pursued in collaboration with the Ovarian Cancer Association Consortium (OCAC) in the future.